Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting over 5 million people in the U.S. No effective treatments are available to prevent, halt, or reverse the disease. Although aging is the most important nongenetic risk factor for AD, young mice have been used for the vast majority of preclinical studies in AD-related mouse models, mainly for practical and financial reasons. Even at young ages, these models share several pathological features with AD. However, they clearly do not simulate the full complexity of the human condition. We hypothesize that aged mouse models will simulate the human condition to a greater extent than young mouse models and that assessing candidate therapies in aged mouse models will better predict the efficacy of these therapies in later clinical trials. In this UH2/UH3 proposal, we will elucidate the phenotypic impact of natural aging in human amyloid precursor protein (hAPP) transgenic mice from line J20?one of the most extensively used AD-related mouse models. In addition, we will compare the efficacy of promising candidate therapies in young and old mice from this line. While strategies targeting amyloid-? (A?) have justifiably received considerable attention over the past decade, it is still unclear whether they will turn out to be both efficacious and safe in ongoing clinical trials. We reported in well-cited publications that treatment with the anti-epileptic drug levetiracetam and genetic reduction of tau ameliorate synaptic, network and cognitive dysfunction in hAPP-J20 mice, and these findings have been confirmed by other groups in independent mouse models. However, it remains to be determine whether these strategies also have beneficial effects in aging brains that have had longer exposures to pathologically elevated levels of A?. We therefore propose to investigate the efficacy of levetiracetam treatment and genetic reduction of tau in old hAPP-J20 mice.